X inactivation skew in a cohort of patients with X-linked inherited retinal disorders. (A) Distribution of haplotype blocks’ skews in multiple samples from patients carrying mutations in the CHM gene (C1–C12) or RPGR gene (R1–R4). (B) Correlations of haplotype blocks’ skew between samples indicates consistency in preferential Xa choice across tissues, for each patient for whom two or more samples show skew (P < 0.4). (C) Summary of tissue skews for each patient. (D) Correlation of buccal skew with phenotypic severity. The skew is classified as either deleterious (variant allele is preferentially Xa), protective (variant allele is preferentially Xi), or neutral (no or little skew, P ≥ 0.4). For six CHM variant carriers with skewed buccal swab samples, the skew could not be oriented (nonoriented category). Retinal severity grading presented in this graph is depicted as grades 1–4 to combine retinal phenotypes for choroideremia and RPGR-associated X-linked retinitis pigmentosa (Edwards et al. 2015; Nanda et al. 2018): grade 1 is fine and normal phenotypes, grade 2 is coarse and radial pattern phenotypes, grade 3 is geographic and focal pigmentary retinopathy phenotypes, and grade 4 is male-pattern phenotypes for choroideremia and RPGR-associated X-linked retinitis pigmentosa, respectively.
